Perivascular regions of the brain harbor multipotent stem cells. We previously demonstrated that brain pericytes near blood vessels also develop multipotency following experimental ischemia in mice and these ischemia-induced multipotent stem cells (iSCs) can contribute to neurogenesis. However, it is essential to understand the traits of iSCs in the poststroke human brain for possible applications in stem cell-based therapies for stroke patients. In this study, we report for the first time that iSCs can be isolated from the poststroke human brain. Putative iSCs were derived from poststroke brain tissue obtained from elderly stroke patients requiring decompressive craniectomy and partial lobectomy for diffuse cerebral infarction. Immunohistochemistry showed that these iSCs were localized near blood vessels within poststroke areas containing apoptotic/necrotic neurons and expressed both the stem cell marker nestin and several pericytic markers. Isolated iSCs expressed these same markers and demonstrated high proliferative potential without loss of stemness. Furthermore, isolated iSCs expressed other stem cell markers, such as Sox2, c-myc, and Klf4, and differentiated into multiple cells in vitro, including neurons. These results show that iSCs, which are likely brain pericyte derivatives, are present within the poststroke human brain. This study suggests that iSCs can contribute to neural repair in patients with stroke.
Get full access to this article
View all access options for this article.
References
1.
MokinM, Kass-HoutT, Kass-HoutO, DumontTM, KanP, SnyderKV, HopkinsLN, SiddiquiAH and LevyEI. (2012). Intravenous thrombolysis and endovascular therapy for acute ischemic stroke with internal carotid artery occlusion: a systematic review of clinical outcomes. Stroke, 43:2362–2368.
2.
ZaidatOO, SuarezJI, SantillanC, SunshineJL, TarrRW, ParasVH, SelmanWR and LandisDM. (2002). Response to intra-arterial and combined intravenous and intra-arterial thrombolytic therapy in patients with distal internal carotid artery occlusion. Stroke, 33:1821–1826.
3.
JacksonEL, Garcia-VerdugoJM, Gil-PerotinS, RoyM, Quinones-HinojosaA, VandenBergS and Alvarez-BuyllaA. (2006). PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron, 51:187–199.
4.
DoetschF, CailleI, LimDA, Garcia-VerdugoJM and Alvarez-BuyllaA. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 97:703–716.
5.
KondoT and RaffM. (2000). Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science, 289:1754–1757.
6.
ShimadaIS, PetersonBM and SpeesJL. (2010). Isolation of locally derived stem/progenitor cells from the peri-infarct area that do not migrate from the lateral ventricle after cortical stroke. Stroke, 41:e552–e560.
ArsenijevicY, VillemureJG, BrunetJF, BlochJJ, DeglonN, KosticC, ZurnA and AebischerP. (2001). Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp Neurol, 170:48–62.
9.
KallurT, DarsaliaV, LindvallO and KokaiaZ. (2006). Human fetal cortical and striatal neural stem cells generate region-specific neurons in vitro and differentiate extensively to neurons after intrastriatal transplantation in neonatal rats. J Neurosci Res, 84:1630–1644.
10.
JooKM, KangBG, YeonJY, ChoYJ, AnJY, SongHS, WonJH, KimSJ, HongSC and NamDH. (2013). Experimental and clinical factors influencing long-term stable in vitro expansion of multipotent neural cells from human adult temporal lobes. Exp Neurol, 240:168–177.
11.
YokoyamaA, SakamotoA, KamedaK, ImaiY and TanakaJ. (2006). NG2 proteoglycan-expressing microglia as multipotent neural progenitors in normal and pathologic brains. Glia, 53:754–768.
12.
NakagomiT, MolnarZ, Nakano-DoiA, TaguchiA, SainoO, KuboS, ClausenM, YoshikawaH, NakagomiN and MatsuyamaT. (2011). Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction. Stem Cells Dev, 20:2037–2051.
13.
NakagomiT, KuboS, Nakano-DoiA, SakumaR, LuS, NaritaA, KawaharaM, TaguchiA and MatsuyamaT. (2015). Brain vascular pericytes following ischemia have multipotential stem cell activity to differntiate into neural and vascular lineage cells. Stem Cells, 33:1962–1974.
14.
NakagomiN, NakagomiT, KuboS, Nakano-DoiA, SainoO, TakataM, YoshikawaH, SternDM, MatsuyamaT and TaguchiA. (2009). Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction. Stem Cells, 27:2185–2195.
15.
NakayamaD, MatsuyamaT, Ishibashi-UedaH, NakagomiT, KasaharaY, HiroseH, Kikuchi-TauraA, SternDM, MoriH and TaguchiA. (2010). Injury-induced neural stem/progenitor cells in post-stroke human cerebral cortex. Eur J Neurosci, 31:90–98.
16.
NakagomiT, KitadaO, KuribayashiK, YoshikawaH, OzawaK, OgawaS and MatsuyamaT. (2004). The 150-kilodalton oxygen-regulated protein ameliorates lipopolysaccharide-induced acute lung injury in mice. Am J Pathol, 165:1279–1288.
17.
NakagomiT, TaguchiA, FujimoriY, SainoO, Nakano-DoiA, KuboS, GotohA, SomaT, YoshikawaH, et al. (2009). Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice. Eur J Neurosci, 29:1842–1852.
18.
Nakano-DoiA, NakagomiT, FujikawaM, NakagomiN, KuboS, LuS, YoshikawaH, SomaT, TaguchiA and MatsuyamaT. (2010). Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction. Stem Cells, 28:1292–1302.
19.
BirbrairA, ZhangT, WangZM, MessiML, EnikolopovGN, MintzA and DelbonoO. (2013). Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells Dev, 22:2298–2314.
20.
SakumaR, KawaharaM, Nakano-DoiA, TakahashiA, TanakaY, NaritaA, Kuwahara-OtaniS, HayakawaT, YagiH, MatsuyamaT and NakagomiT. (2016). Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. J Neuroinflammation, 13:57.
21.
WystrychowskiW, PatlollaB, ZhugeY, NeofytouE, RobbinsRC and BeyguiRE. (2016). Multipotency and cardiomyogenic potential of human adipose-derived stem cells from epicardium, pericardium, and omentum. Stem Cell Res Ther, 7:84.
22.
NakataM, NakagomiT, MaedaM, Nakano-DoiA, MomotaY and MatsuyamaT. (2017). Induction of Perivascular Neural Stem Cells and Possible Contribution to Neurogenesis Following Transient Brain Ischemia/Reperfusion Injury. Transl Stroke Res, 8:131–143.
23.
MokryJ, CizkovaD, FilipS, EhrmannJ, OsterreicherJ, KolarZ and EnglishD. (2004). Nestin expression by newly formed human blood vessels. Stem Cells Dev, 13:658–664.
24.
SuzukiS, NamikiJ, ShibataS, MastuzakiY and OkanoH. (2010). The neural stem/progenitor cell marker nestin is expressed in proliferative endothelial cells, but not in mature vasculature. J Histochem Cytochem, 58:721–730.
25.
EtcheversHC, VincentC, Le DouarinNM and CoulyGF. (2001). The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development, 128:1059–1068.
26.
CimadamoreF, FishwickK, GiustoE, GnedevaK, CattarossiG, MillerA, PluchinoS, BrillLM, Bronner-FraserM and TerskikhAV. (2011). Human ESC-derived neural crest model reveals a key role for SOX2 in sensory neurogenesis. Cell Stem Cell, 8:538–551.
27.
NakagomiT, Nakano-DoiA, KawamuraM and MatsuyamaT. (2015). Do vascular pericytes contribute to neurovasculogenesis in the central nervous system as multipotent vascular stem cells?. Stem Cells Dev, 24:1730–1739.
28.
FengJ, MantessoA, De BariC, NishiyamaA and SharpePT. (2011). Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proc Natl Acad Sci U S A, 108:6503–6508.
29.
CaplanAI. (2008). All MSCs are pericytes?. Cell Stem Cell, 3:229–230.
30.
CorselliM, ChenCW, CrisanM, LazzariL and PeaultB. (2010). Perivascular ancestors of adult multipotent stem cells. Arterioscler Thromb Vasc Biol, 30:1104–1109.
31.
CrisanM, YapS, CasteillaL, ChenCW, CorselliM, ParkTS, AndrioloG, SunB, ZhengB, et al. (2008). A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell, 3:301–313.
32.
CalloniGW, Glavieux-PardanaudC, Le DouarinNM and DupinE. (2007). Sonic Hedgehog promotes the development of multipotent neural crest progenitors endowed with both mesenchymal and neural potentials. Proc Natl Acad Sci U S A, 104:19879–19884.
33.
CalloniGW, Le DouarinNM and DupinE. (2009). High frequency of cephalic neural crest cells shows coexistence of neurogenic, melanogenic, and osteogenic differentiation capacities. Proc Natl Acad Sci U S A, 106:8947–8952.
34.
Wislet-GendebienS, LaudetE, NeirinckxV, AlixP, LeprinceP, GlejzerA, PouletC, HennuyB, SommerL, ShakhovaO and RogisterB. (2012). Mesenchymal stem cells and neural crest stem cells from adult bone marrow: characterization of their surprising similarities and differences. Cell Mol Life Sci, 69:2593–2608.
35.
IsernJ, Garcia-GarciaA, MartinAM, ArranzL, Martin-PerezD, TorrojaC, Sanchez-CaboF and Mendez-FerrerS. (2014). The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function. Elife, 3:e03696.
KabaraM, KawabeJ, MatsukiM, HiraY, MinoshimaA, ShimamuraK, YamauchiA, AonumaT, NishimuraM, et al. (2014). Immortalized multipotent pericytes derived from the vasa vasorum in the injured vasculature. A cellular tool for studies of vascular remodeling and regeneration. Lab Invest, 94:1340–1354.
38.
BirbrairA, ZhangT, WangZM, MessiML, EnikolopovGN, MintzA and DelbonoO. (2012). Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res, 10:67–84.
39.
BirbrairA, ZhangT, WangZM, MessiML, MintzA and DelbonoO. (2014). Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Front Aging Neurosci, 6:245.
40.
Farrington-RockC, CroftsNJ, DohertyMJ, AshtonBA, Griffin-JonesC and CanfieldAE. (2004). Chondrogenic and adipogenic potential of microvascular pericytes. Circulation, 110:2226–2232.
41.
DarA, DomevH, Ben-YosefO, TzukermanM, Zeevi-LevinN, NovakA, GermanguzI, AmitM and Itskovitz-EldorJ. (2012). Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation, 125:87–99.
42.
DohertyMJ, AshtonBA, WalshS, BeresfordJN, GrantME and CanfieldAE. (1998). Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res, 13:828–838.
43.
BirbrairA, ZhangT, WangZM, MessiML, OlsonJD, MintzA and DelbonoO. (2014). Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol, 307:C25–C38.
44.
Nakano-DoiA, NakagomiT, SakumaR, TakahashiA, TanakaY, KawamuraM and MatsuyamaT. (2016). Expression patterns and phenotypic changes regarding stemness in brain pericytes in health and disease. J Stem Cell Res Ther. 6.
45.
VojnitsK, PanH, MuX and LiY. (2015). Characterization of an injury induced population of muscle-derived stem cell-like cells. Sci Rep, 5:17355.
TropelP, NoelD, PlatetN, LegrandP, BenabidAL and BergerF. (2004). Isolation and characterisation of mesenchymal stem cells from adult mouse bone marrow. Exp Cell Res, 295:395–406.
48.
PaulG, OzenI, ChristophersenNS, ReinbotheT, BengzonJ, VisseE, JanssonK, DannaeusK, Henriques-OliveiraC, et al. (2012). The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS One, 7:e35577.
49.
HonmaT, HonmouO, IihoshiS, HaradaK, HoukinK, HamadaH and KocsisJD. (2006). Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp Neurol, 199:56–66.
50.
ZhouF, GaoS, WangL, SunC, ChenL, YuanP, ZhaoH, YiY, QinY, et al. (2015). Human adipose-derived stem cells partially rescue the stroke syndromes by promoting spatial learning and memory in mouse middle cerebral artery occlusion model. Stem Cell Res Ther, 6:92.
51.
FischerUM, HartingMT, JimenezF, Monzon-PosadasWO, XueH, SavitzSI, LaineGA and CoxCSJr. (2009). Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev, 18:683–692.
52.
SainoO, TaguchiA, NakagomiT, Nakano-DoiA, KashiwamuraS, DoeN, NakagomiN, SomaT, YoshikawaH, et al. (2010). Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J Neurosci Res, 88:2385–2397.
53.
TakataM, NakagomiT, KashiwamuraS, Nakano-DoiA, SainoO, NakagomiN, OkamuraH, MimuraO, TaguchiA and MatsuyamaT. (2012). Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke. Cell Death Differ, 19:756–767.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
